CD56(BRIGHT) NATURAL-KILLER-CELL SUBSETS - CHARACTERIZATION OF DISTINCT FUNCTIONAL-RESPONSES TO INTERLEUKIN-2 AND THE C-KIT LIGAND

Natural killer (NK) cells are bone marrow-derived large granular lymph ocytes that express the CD56 surface antigen. The CD56(bright) NK subs et represents approximately 10% of all NK cells and is thought to be t he least differentiated NK cell component in blood. The most mature NK cell expresses CD56 at low density and CD16 (FcR gamma III) at high d ensity, whereas CD56(bright) NK cells either lack CD16 (CD56(bright) C D16(-)) or express it at low density (CD56(bright) CD16(dim)). c-kit i s a tyrosine kinase receptor which is expressed on both CD34(+) hemato poietic precursor cells and CD56(bright) NK cells. In the current stud y, we characterize interleukin (IL)-2 receptor (IL-2R) and c-kit expre ssion in each of the CD56(bright) subsets. Both the CD56(bright) CD16( -) and CD56(bright) CD16(dim) NK subsets express the high-affinity IL- 2R and the c-kit receptor when isolated from fresh blood. However, eac h CD56(bright) NK cell subset has distinct functional responses to IL- 2, the c-kit ligand (KL), or both. Activation of the high-affinity IL- 2R on CD56(bright) CD16(-) NK cells induces a proliferative response t hat is significantly weaker than that observed in the CD56(bright) CD1 6(dim) NK cell subset. Incubation of the CD56(bright) CD16(-) NK cell subset with KL significantly enhances IL-2-induced proliferation, whil e KL has no such effect on the CD56(bright) CD16(dim) NK subset. Activ ation of the high-affinity IL-2R in both CD56(bright) subsets induces lymphokine-activated killer (LAK) activity, but the addition of KL has no effect on LAK activity. Co-stimulation of either CD56(bright) subs et with IL-12 and concentrations of IL-2 that only saturate the high-a ffinity IL-2R induces substantial interferon (IFN)-gamma production. T he addition of KL to this co-stimulatory signal enhances IFN-gamma pro duction in both CD56(bright) NK subsets. The distinct functional respo nses to IL-2 and KL seen in the CD56(bright) CD16(-) and CD56(bright) CD16(dim) NK subsets provide insight into IL-2R signaling and suggest that each phenotype identifies a discrete stage of NK cell differentia tion.